The IgE network is associated with immunity to parasitic infection and with the allergic response. The interaction of IgE antibodies with two receptors, FceRI and CD23, couples the diversity of the IgE repertoire to effector cells of the immune system. Effector functions triggered by IgE:antigen complexes include the activation of mast cells, basophils and eosinophils, the feedback regulation of IgE production and the introduction of antigen into MHC class II antigen presentation pathways. We have previously elucidated the crystal structures of the ectodomains of the high affinity IgE receptor (FceRIa), the IgE-Fc Ce3/Ce4 domains and the complex of the IgE-Fc bound to FceRIa. The structures have provided new insights into the interactions between these two proteins and raised additional questions relevant to our understanding of IgE function and the development of new therapeutic approaches to treating allergic diseases. The aims of this proposal are to investigate new leads for developing inhibitors of the IgE-Fc:FceRIcx interaction, based on previous structural and biochemical observations. In addition, the role of IgE-Fc conformational transitions in binding interactions with both FceRI and CD23 will be explored using mutagenesis and X-ray crystallography. Further crystallographic studies of the interaction of IgE with both of its receptors will be pursued, in an effort to elucidate basic new mechanisms in antibody biology, with relevance to our understanding and treatment of atopic diseases.